Toxicological Properties of Potassium Bromate
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macolog ar ic h a P l f R o e l p a o Starek, Starek-Swiechowicz, J Pharma Reports n r r t s u o J Journal of Pharmacological Reports 2016, 1:3 Review Article Open Access Toxicological Properties of Potassium Bromate Andrzej Starek* and Beata Starek-Świechowicz Department of Biochemical Toxicology, Chair of Toxicology, Medical College, Jagiellonian Uniwersity, Kraków, Poland *Corresponding author: Andrzej Starek, Department of Biochemical Toxicology, Chair of Toxicology, Medical College, Jagiellonian Uniwersity, Kraków, Poland, Tel: +48 12 422 10 33; E-mail: [email protected] Received date: May 30, 2016; Accepted date: July 12, 2016; Published date: July 15, 2016 Copyright: © 2016 Starek A, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract Potassium bromate (KBrO3), used in both the food and cosmetics industry, and a drinking water disinfection by- product, is a nephrotoxic chemical and rodent carcinogen. As KBrO3 is primarily an oxidizing compound, reactive oxygen and other species generated from bromate have been held responsible for the genotoxic, carcinogenic and toxic effects. Bromate induces primary DNA oxidative damage, mutations, and DNA-strand breakage, structural chromosomal aberration types of chromatid breaks and exchanges. KBrO3 induces of micronuclei in different cells in vivo. Bromate is clastogenic agent. Bromate administered in the drinking water was tumorogenic in the rat kidney, thyroid, and mesothelium and was a renal carcinogen in the male mouse. The incidence of mesotheliomas on the tunica vaginalis testis in rats was a dose-dependent manner. It was shown that KBrO3 is an effective promoter of kidney neoplasia induced by N-ethyl-N-hydroxyethylnitrosamine. There are a lot naturally occurring compounds which may be used as effective chemopreventive agents against KBrO3-mediated renal and other organ oxidative stress, toxicity and tumor promotion response. Keywords: Potassium bromate; Oxidative damages; Genotoxicity; hairdressers [1]. The lethal dose of this chemical in man has been Carcinogenicity; Chemoprotection estimated at 5-500 mg/kg of body weight (b.w.) [4,5]. In reported cases nine out of twenty four adults died 3-5 days after ingestion [5]. Introduction In the acute phase of poisoning, vomiting and diarrhea with abdominal pain were the main symptoms. Subsequent manifestations Potassium bromate (KBrO3; CAS No. 7758-01-2) is not a naturally occurring compound, but is synthesied by passing bromine vapour included oliguria, anuria, deafness, thrombocytopenia, hypotension, through a solution of potassium hydroxide when heated. This vertigo, and depression of the central nervous system. Acute renal compound exists as white crystals, crystalline powder or granules. It is failure was associated with hemolytic uremic syndrome [4]. In both highly soluble in water (75 g/L at 25ºC), slightly soluble in ethanol; it is children and adults, oliguria and death from renal failure were seen [4]. very stable in water solution at room temperature. KBrO3 decomposes at temperature above 370ºC, with the emission of oxygen and toxic In biopsy of the kidney atrophy, necrosis, degeneration, and fumes [1]. regeneration of the proximal tubular epithelim have often been observed. In the later stages, sclerosis of the glomeruli and interstitial KBrO3 is a strong oxidizing agent that has been used in flour milling, as an ingredient in fish-paste in Japan, in cheese making, in fibrosis have been reported. Cardiotoxicity and hepatotoxicity have beer malting, and as a component of cold hair-wave liquids, and a also been observed [5]. oxidizing compound [1]. Partial hearing loss and complete deafness have also been reported Moreover, bromate is formed as a by-product of water disinfection [4,6]. Severe irreversible sensorineural hearing loss within 4-16 h of by ozonation and is frequently detected in top and bottled water. In bromate ingestion was recorded in almost all of the cases. Moreover, fact bromate is one of the most prevalent disinfection by-product of strong irritating action of KBrO3 on gastric mucosa was noted [6,7]. surface water [2]. The signs and symptoms of chronic intoxication of humans by KBrO3 have not been described. Ozone has been introduced for water disinfection because it is more efficient than chlorine for killing microbes and leads to much lower Toxicity in experimental animals levels of carcinogenic trihalomethanes (THMs). Ozone leads to formation of hydrobromous acid in water with high bromine content The values of median lethal doses (LD50) per os of KBrO3 in rats, and forms brominated organic by-products and bromate [3]. mice, and hamsters (Table 1) were comprised the range of 280 to 495 Occupational exposure to KBrO3 occurs mainly in production plants mg/kg of body weight [1]. Other data indicate that the oral LD50 value during packaging processes. of this compound in rats, determined by OECD Guideline 401 method, was estimated at level of 157 mg/kg b.w. Potassium bromate Toxicity in humans has been classified as a compound belonging to the category “Toxic” [8]. In Western countries most poison cases with KBrO3 were by Major toxic signs and symptoms after a single intragastric accidental ingestion, mainly among children. In Japan, KBrO3 was more often ingested for tentative suicide by young women, especially administration of KBrO3 were tachypnoea, hypotermia, diarrhea, J Pharma Reports, an open access journal Volume 1 • Issue 3 • 1000122 Citation: Starek, Starek-Swiechowicz (2016) Toxicological Properties of Potassium Bromate. J Pharma Reports 1: 122. Page 2 of 9 lacrimation, piloerection, suppression of locomotor movement, ataxic mg/kg-day) group following 2- and 13-weeks exposure. In renal gait, and animals lying in a prone position. At autopsy the major tubules of rats exposed to 16.2 and 32.4 mg/kg-day of KBrO3 for 2 findings were strong hyperemia of the glandular stomach mucosa and weeks and in rats of the 32.4 mg/kg-day group at 13 weeks hyaline congestion of the lung. Microscopically, epithelial dilatation and droplets were seen. A no observed effect level (NOEL) of 8.1 mg/kg- desquamation of the distal convoluted tubules were observed in rats 1 day was selected on the base of the absence of microscopic alterations h after KBrO3 administration. Necrosis and degenerative changes of in the kidney [14]. the proximal tubular epithelium were noted after 3 h and regenerative Eighteen rats, three dogs, and three monkeys were fed a diet alterations of the tubular epithelium occured within 48 h. In mice and containing 84% flour treated with KBrO at a level of 75 mg/kg for a hamsters, however, these histopatological changes were later observed 3 period of 4, 12 and 8 weeks respectively. No adverse effects were found and to a lesser intensity [1]. A nephrotoxic single dose of KBrO (100 3 in any of the species. Twelve rats and two dogs were fed with bread mg/kg b.w.) administered to rats resulted in a decline in the specific made from flour containing 200 mg/kg KBrO for 16 days, and three activities of leucine aminopeptidase (LAP), γ-glutamyl transferase (γ- 3 dogs given diets containing flour treated with 70 mg/kg KBrO for 6 GT), maltase, and alkaline phosphatase (AP), enzymes of brush border 3 weeks, and also four dogs were given bread made from flour membrane (BBM), and also induced oxidative stress in kidney. The containing 200 mg/kg KBrO for 17 months showed no adverse effects enzymes of carbohydrate metabolism, i.e., lactate dehydrogenase, 3 associated with the intake diets [15]. malate dehydrogenase, glucose-6-phosphate dehydrogenase, glucose-6-phosphatase, and fructose-1,6-bisphosphatase were also altered and suggest a shift in energy metabolism from the aerobic to Mutagenicity and genotoxicity anaerobic mode. Maximum changes in all the parameters were 48 h No data were available on the subject of mutagenicity and after administration of KBrO3, after which recovery took place [9]. genotoxicity in humans. Potassium bromate was found to be weakly mutagenic in Salmonella typhimurium TA100 at a concentration of 3 Species/Strain Male Female mg/plate after metabolic activation. However, the compound proved Rat F344 400 (348-460)a 495 (446-549) not mutagenic active in S. typhimurium TA98, TA1535, TA1537, TA1538, Escherichia coli WP2try- and E. coli WP2try-his- with or Rat Wistar 157 157 without metabolic activation [16,17]. KBrO3 was also mutagenic in S. Mouse B6C3F1 280 (250-314) 355 (311-405) typhimurium TA102 and TA104, strains which are sensitive to chemicals that generate reactive oxygen species (ROS) and active Mouse MS/Ae 471 - oxygen radicals [18]. Mouse CD-1 289 - Potassium bromate as a strong oxidant induces primary DNA oxidative damage. KBrO3 increases 8-hydroxydeoxyguanosine (8-OH- Hamster Syrian golden 388 (318-473) 460 (400-529) dG) DNA adduct levels, a representative marker of oxidative DNA modification, in vivo and in vitro [19-21]. Under cell-free conditions, Table 1: LD50 (mg/kg b.w.) values in rat, mouse, and hamster after p.o. no modification was induced by KBrO3 alone, but evident DNA administration [1,8]. aNumbers in parentheses are 95% confidence damage was seen in the presence of reduced glutathione (GSH). In limits. Observation time amounted 7 days. L1210 mouse leukemia cells and LLC-PK1 porcine kidney cells, KBrO3 led to a DNA damage profile similar to that observed after treatment of In the same experiment similar effects were observed in the cell-free DNA with bromate and GSH [22]. Speit et al. [23], using the intestinal mucosa [10]. KBrO3 administered to rats resulted in Comet assay in V79 Chinese hamster cells treated with KBrO3, found increased lipid peroxidation, protein oxidation, hydrogen peroxide that this chemical significantly increased levels of 8-OHdG.